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Cancer Cell

Jinchul Kim, Lili Yu, Wancheng Chen, Yanxia Xu, Meng Wu, Dilyana Todorova, Qingshuang Tang, Bingbing Feng, Lei Jiang, Jingjin He, Guihua Chen, Xuemei Fu, Yang Xu
The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier (MPC) through PUMA-MPC interaction, which depends on IκB kinase-mediated phosphorylation of PUMA at Ser96/106...
January 16, 2019: Cancer Cell
Hideaki Ogiwara, Kazuaki Takahashi, Mariko Sasaki, Takafumi Kuroda, Hiroshi Yoshida, Reiko Watanabe, Ami Maruyama, Hideki Makinoshima, Fumiko Chiwaki, Hiroki Sasaki, Tomoyasu Kato, Aikou Okamoto, Takashi Kohno
ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species...
January 16, 2019: Cancer Cell
Shanye Yin, Rutendo G Gambe, Jing Sun, Aina Zurita Martinez, Zachary J Cartun, Fara Faye D Regis, Youzhong Wan, Jean Fan, Angela N Brooks, Sarah E M Herman, Elisa Ten Hacken, Amaro Taylor-Weiner, Laura Z Rassenti, Emanuela M Ghia, Thomas J Kipps, Esther A Obeng, Carrie L Cibulskis, Donna Neuberg, Dean R Campagna, Mark D Fleming, Benjamin L Ebert, Adrian Wiestner, Ignaty Leshchiner, James A DeCaprio, Gad Getz, Robin Reed, Ruben D Carrasco, Catherine J Wu, Lili Wang
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases...
January 14, 2019: Cancer Cell
Ashton A Connor, Robert E Denroche, Gun Ho Jang, Mathieu Lemire, Amy Zhang, Michelle Chan-Seng-Yue, Gavin Wilson, Robert C Grant, Daniele Merico, Ilinca Lungu, John M S Bartlett, Dianne Chadwick, Sheng-Ben Liang, Jenna Eagles, Faridah Mbabaali, Jessica K Miller, Paul Krzyzanowski, Heather Armstrong, Xuemei Luo, Lars G T Jorgensen, Joan M Romero, Prashant Bavi, Sandra E Fischer, Stefano Serra, Sara Hafezi-Bakhtiari, Derin Caglar, Michael H A Roehrl, Sean Cleary, Michael A Hollingsworth, Gloria M Petersen, Sarah Thayer, Calvin H L Law, Sulaiman Nanji, Talia Golan, Alyssa L Smith, Ayelet Borgida, Anna Dodd, David Hedley, Bradly G Wouters, Grainne M O'Kane, Julie M Wilson, George Zogopoulos, Faiyaz Notta, Jennifer J Knox, Steven Gallinger
We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants...
January 9, 2019: Cancer Cell
Serap Erkek, Pascal D Johann, Martina A Finetti, Yiannis Drosos, Hsien-Chao Chou, Marc Zapatka, Dominik Sturm, David T W Jones, Andrey Korshunov, Marina Rhyzova, Stephan Wolf, Jan-Philipp Mallm, Katja Beck, Olaf Witt, Andreas E Kulozik, Michael C Frühwald, Paul A Northcott, Jan O Korbel, Peter Lichter, Roland Eils, Amar Gajjar, Charles W M Roberts, Daniel Williamson, Martin Hasselblatt, Lukas Chavez, Stefan M Pfister, Marcel Kool
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states...
December 12, 2018: Cancer Cell
Qingfei Jiang, Jane Isquith, Maria Anna Zipeto, Raymond H Diep, Jessica Pham, Nathan Delos Santos, Eduardo Reynoso, Julisia Chau, Heather Leu, Elisa Lazzari, Etienne Melese, Wenxue Ma, Rongxin Fang, Mark Minden, Sheldon Morris, Bing Ren, Gabriel Pineda, Frida Holm, Catriona Jamieson
Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation...
December 11, 2018: Cancer Cell
Jon D Larson, Lawryn H Kasper, Barbara S Paugh, Hongjian Jin, Gang Wu, Chang-Hyuk Kwon, Yiping Fan, Timothy I Shaw, André B Silveira, Chunxu Qu, Raymond Xu, Xiaoyan Zhu, Junyuan Zhang, Helen R Russell, Jennifer L Peters, David Finkelstein, Beisi Xu, Tong Lin, Christopher L Tinkle, Zoltan Patay, Arzu Onar-Thomas, Stanley B Pounds, Peter J McKinnon, David W Ellison, Jinghui Zhang, Suzanne J Baker
Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes...
December 11, 2018: Cancer Cell
Minhong Shen, Yi-Zhou Jiang, Yong Wei, Brian Ell, Xinlei Sheng, Mark Esposito, Jooeun Kang, Xiang Hang, Hanqiu Zheng, Michelle Rowicki, Lanjing Zhang, Weichung J Shih, Toni Celià-Terrassa, Yirong Liu, IIeana Cristea, Zhi-Ming Shao, Yibin Kang
Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways...
December 10, 2018: Cancer Cell
Panagiotis Karras, Erica Riveiro-Falkenbach, Estela Cañón, Cristina Tejedo, Tonantzin G Calvo, Raúl Martínez-Herranz, Direna Alonso-Curbelo, Metehan Cifdaloz, Eva Perez-Guijarro, Gonzalo Gómez-López, Pilar Ximenez-Embun, Javier Muñoz, Diego Megias, David Olmeda, Jorge Moscat, Pablo L Ortiz-Romero, Jose L Rodríguez-Peralto, María S Soengas
Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner...
December 1, 2018: Cancer Cell
Courtney L Jones, Brett M Stevens, Angelo D'Alessandro, Julie A Reisz, Rachel Culp-Hill, Travis Nemkov, Shanshan Pei, Nabilah Khan, Biniam Adane, Haobin Ye, Anna Krug, Dominik Reinhold, Clayton Smith, James DeGregori, Daniel A Pollyea, Craig T Jordan
No abstract text is available yet for this article.
February 11, 2019: Cancer Cell
Kunihiko Hinohara, Hua-Jun Wu, Sébastien Vigneau, Thomas O McDonald, Kyomi J Igarashi, Kimiyo N Yamamoto, Thomas Madsen, Anne Fassl, Shawn B Egri, Malvina Papanastasiou, Lina Ding, Guillermo Peluffo, Ofir Cohen, Stephen C Kales, Madhu Lal-Nag, Ganesha Rai, David J Maloney, Ajit Jadhav, Anton Simeonov, Nikhil Wagle, Myles Brown, Alexander Meissner, Piotr Sicinski, Jacob D Jaffe, Rinath Jeselsohn, Alexander A Gimelbrant, Franziska Michor, Kornelia Polyak
No abstract text is available yet for this article.
February 11, 2019: Cancer Cell
Matthew D Hellmann, Margaret K Callahan, Mark M Awad, Emiliano Calvo, Paolo A Ascierto, Akin Atmaca, Naiyer A Rizvi, Fred R Hirsch, Giovanni Selvaggi, Joseph D Szustakowski, Ariella Sasson, Ryan Golhar, Patrik Vitazka, Han Chang, William J Geese, Scott J Antonia
No abstract text is available yet for this article.
February 11, 2019: Cancer Cell
Yong Tao, Byunghak Kang, Daniel A Petkovich, Yuba R Bhandari, Julie In, Genevieve Stein-O'Brien, Xiangqian Kong, Wenbing Xie, Nicholas Zachos, Shinji Maegawa, Himani Vaidya, Stephen Brown, Ray-Whay Chiu Yen, Xiaojian Shao, Jai Thakor, Zhihao Lu, Yi Cai, Yuezheng Zhang, Izaskun Mallona, Miguel Angel Peinado, Cynthia A Zahnow, Nita Ahuja, Elana Fertig, Jean-Pierre Issa, Stephen B Baylin, Hariharan Easwaran
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E , producing the typical human proximal BRAFV600E -driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP)...
February 11, 2019: Cancer Cell
Ksenia Skvortsova, Etienne Masle-Farquhar, Phuc-Loi Luu, Jenny Z Song, Wenjia Qu, Elena Zotenko, Cathryn M Gould, Qian Du, Timothy J Peters, Yolanda Colino-Sanguino, Ruth Pidsley, Shalima S Nair, Amanda Khoury, Grady C Smith, Lisa A Miosge, Joanne H Reed, James G Kench, Mark A Rubin, Lisa Horvath, Ozren Bogdanovic, Sue Mei Lim, Jose M Polo, Christopher C Goodnow, Clare Stirzaker, Susan J Clark
Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5' or 3' CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. We show that the pattern of H3K4me1 at CpG island borders in normal cells predicts the different modes of cancer CpG island hypermethylation...
February 11, 2019: Cancer Cell
Judith E Grolleman, Richarda M de Voer, Fadwa A Elsayed, Maartje Nielsen, Robbert D A Weren, Claire Palles, Marjolijn J L Ligtenberg, Janet R Vos, Sanne W Ten Broeke, Noel F C C de Miranda, Renske A Kuiper, Eveline J Kamping, Erik A M Jansen, M Elisa Vink-Börger, Isabell Popp, Alois Lang, Isabel Spier, Robert Hüneburg, Paul A James, Na Li, Marija Staninova, Helen Lindsay, David Cockburn, Olivera Spasic-Boskovic, Mark Clendenning, Kevin Sweet, Gabriel Capellá, Wenche Sjursen, Hildegunn Høberg-Vetti, Marjolijn C Jongmans, Kornelia Neveling, Ad Geurts van Kessel, Hans Morreau, Frederik J Hes, Rolf H Sijmons, Hans K Schackert, Clara Ruiz-Ponte, Dagmara Dymerska, Jan Lubinski, Barbara Rivera, William D Foulkes, Ian P Tomlinson, Laura Valle, Daniel D Buchanan, Sue Kenwrick, Julian Adlard, Aleksandar J Dimovski, Ian G Campbell, Stefan Aretz, Detlev Schindler, Tom van Wezel, Nicoline Hoogerbrugge, Roland P Kuiper
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%)...
February 11, 2019: Cancer Cell
Tuba N Gide, Camelia Quek, Alexander M Menzies, Annie T Tasker, Ping Shang, Jeff Holst, Jason Madore, Su Yin Lim, Rebecca Velickovic, Matthew Wongchenko, Yibing Yan, Serigne Lo, Matteo S Carlino, Alexander Guminski, Robyn P M Saw, Angel Pang, Helen M McGuire, Umaimainthan Palendira, John F Thompson, Helen Rizos, Ines Pires da Silva, Marcel Batten, Richard A Scolyer, Georgina V Long, James S Wilmott
Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments...
February 11, 2019: Cancer Cell
Hongwei Du, Koichi Hirabayashi, Sarah Ahn, Nancy Porterfield Kren, Stephanie Ann Montgomery, Xinhui Wang, Karthik Tiruthani, Bhalchandra Mirlekar, Daniel Michaud, Kevin Greene, Silvia Gabriela Herrera, Yang Xu, Chuang Sun, Yuhui Chen, Xingcong Ma, Cristina Rosa Ferrone, Yuliya Pylayeva-Gupta, Jen Jen Yeh, Rihe Liu, Barbara Savoldo, Soldano Ferrone, Gianpietro Dotti
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3...
February 11, 2019: Cancer Cell
Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G Malouf, Xiaoping Su, Liren Li, Dolores Lopez-Terrada, Dinesh Rakheja, Alexander J Lazar, George J Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N Tripathi, Cheryl L Walker, Jose A Karam, Timothy P Heffernan, Andrea Viale, Charles W M Roberts, Pavlos Msaouel, Nizar M Tannir, Giulio F Draetta, Giannicola Genovese
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF -p53 axis...
February 11, 2019: Cancer Cell
Lu Wang, Ali Shilatifard
Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear...
February 11, 2019: Cancer Cell
Toshikazu Ushijima, Hiromu Suzuki
In this issue of Cancer Cell, Tao et al. provide compelling evidence that aging-like DNA methylation of multiple CpG islands, the CpG island methylator phenotype (CIMP), produces a cellular context that can tolerate BRAF activation avoiding senescence by dedicating 5-month culture of colon-derived organoids to epigenomic and stemness analysis.
February 11, 2019: Cancer Cell
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